Patent GB-488801-A (GB)
Title: Process for the preparation of testosterone and its esters
IPC: C07J1/00
Filed: 1937-02-04
Abstract: Testosterone is prepared from dehydroandrosterone by a process which comprises: The formation of a triarylcarbinol ether of trans-dehydroandrosterone, the reduction of this keto-ether to the corresponding hydroxy-ether, in alkaline solution, the esterification of the hydroxy group, the removal of the ether p  group by acid hydrolysis, and the oxidation of the hydroxy group at position -3 into a keto group to yield a 17-ester of testosterone.  The free hydroxy-ketone may be regenerated by hydrolysis if desired.  The nuclear double bond is protected by the addition of halogen during the oxidation stage.  The esterification of the hydroxy-ether is preferably done in the presence of a tertiary base such as pyridine. It is unnecessary to remove the triarylcarbinol formed in the acid hydrolysis since this substance does not interfere with subsequent steps, and the testosterone is easily purified after removal of the halogen protection for the nuclear double bond by the use of ketone reagents, particularly trimethyl-acethydrazide-ammonium.  In examples: (1) trans-dehydroandrosterone is treated with triphenylmethyl chloride in the presence of pyridine to give the triphenylmethyl ether of dehydroandrosterone which is purified by crystallization before being dissolved in propanol and reduced with metallic sodium to the hydroxy ether.  This compound is esterified either by acetic anhydride in the presence of pyridine, or by treatment with ketene in anhydrous ether solution to give the triphenylmethyl ether of 17 - acetyl - androstendiol.  The removal of the ether group is easily effected without any attack on the 17-acetyl group by treatment with dilute sulphuric acid in acetone. The mixture of triphenylcarbinol and acetyl-17-androstene diol is treated with bromine and then oxidized with chromic acid.  After the oxidation the product is treated with zinc filings, and the zinc bromide decomposed with lead acetate.  The lead bromide is filtered and the solution treated with trimethyl - acetylhydrazide - ammonium, which forms a water soluble compound with testosterone acetate.  The reaction mixture on dilution with a large bulk of water deposits the triphenyl carbinol, which is filtered and then sulphuric acid added to hydrolyze the hydrazine compound.  After 12 hours the testosterone acetate is extracted with ether and if desired hydrolyzed to testosterone.  (2) The triphenylmethyl ether of androstendiol obtained as in example (1) is treated with benzoyl chloride, and the excess of acid chloride removed by sodium ethylate.  The androstendiol-17-acetate-3-triphenylmethyl ether is then worked up as in example (1).  Instead of triphenyl - carbinol, there may be used homologues thereof such as tritolyl carbinol.  (3) Dibromocholesteryl acetate is oxidized with chromic oxide and etherified with triphenyl-chloromethane in the presence of pyridine, and treated with sodium in propanol to give androstendiol triphenylmethyl ether, which is then treated as in example (1) to give testosterone.  Reference has been directed by the Comptroller to Specification 467,161.